Vitamin E supplement use was associated with decreased risk of cardiovascular events inthe Nurses' Health Study, but the mechanism of benefit is unknown. However, therapies that reduce cardiovascular risk have commonly been found to improve endothelial function in postmenopausal women and whether this effect is comparable or additive to that of estrogen therapy, also associated with reduced risk in the Nurses' Health Study, we administered vitamin E 800 IU, conjugated equine estrogen (CEE) 0.625 mg, or the combination daily, each for 6 weeks to 28 postmenopausal women in a randomized, ouble-blind, double- crossover study. We measured brachial artery flow-mediated dilation following forearm ischemia as a bioassay of endothelial nitric oxide release and endothelium-independent dilation after nitroglycerin (NTG). Equivalent improvement in flow-mediated dilation was seen with each therapy from respective pretreatment values (mean+/-SD: vitamin E 4.5+/-3.4 to 8.9+/-2.9%, p<0.001; CEE 4.3+/-2.7 to 8.8+/-4.0%, p<0.001; vitamin E/CEE 4.0+/-1.7 to 9.3+/-3.6%, p<0.001; there were no differences among these therapies on flow-mediated dilation (p=0.267 by ANOVA). There was no effect of therapies on vasodilation after NTG: vitamin E 14.7+/-3.7 to 14.8+/-3.6%, p=0.941; CEE 15.1+/-3.7 to 14.8+/-3.6%, p=0.941; CEE 15.1+/-3.7 to 14.5+/-5.7%, p=0.600; vitamin E/CEE 14.1+/-3.8 to 15.1+/-3.0%, p=0.235), and there were no differences among therapies (p=0.362 by ANOVA). Thus, vitamin E specifically improves endothelium-dependent vasodilation in postmenopausal women, an effect comparable to CEE, but without additive effects when therapies are combined. Improvement in endothelium-dependent nitric oxide bioactivity may account in part for the cardiovascular benefit of vitamin E supplement use by postmenopausal women.